Acalabrutinib (ACP-196)
featured

    WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 206112

CAS#: 1420477-60-6 (free base)

Description: Acalabrutinib, also known as ACP-196, is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, ACP-196 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.


Chemical Structure

img
Acalabrutinib (ACP-196)
CAS# 1420477-60-6 (free base)

Theoretical Analysis

MedKoo Cat#: 206112
Name: Acalabrutinib (ACP-196)
CAS#: 1420477-60-6 (free base)
Chemical Formula: C26H23N7O2
Exact Mass: 465.19132
Molecular Weight: 465.52
Elemental Analysis: C, 67.08; H, 4.98; N, 21.06; O, 6.87

Price and Availability

Size Price Availability Quantity
50.0mg USD 90.0 Ready to ship
100.0mg USD 150.0 Ready to ship
200.0mg USD 250.0 Ready to ship
500.0mg USD 550.0 Ready to ship
1.0g USD 950.0 Ready to ship
2.0g USD 1650.0 Ready to ship
Bulk inquiry

Related CAS #: 1420477-60-6 (free base)   2242394-65-4 (maleate)   2058091-93-1 (3 hydrate)   2058091-94-2 (fumarate)   2058091-96-4 (phosphate)   2058091-99-7 (citrate)   2058091-97-5 (tartrate)   2058092-05-8 (sulfate)  

Synonym: ACP-196; ACP196; ACP 196; Acalabrutinib

IUPAC/Chemical Name: (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide

InChi Key: WDENQIQQYWYTPO-IBGZPJMESA-N

InChi Code: InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1

SMILES Code: O=C(NC1=NC=CC=C1)C2=CC=C(C3=C4C(N)=NC=CN4C([C@H]5N(C(C#CC)=O)CCC5)=N3)C=C2

Appearance: Yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Acalabrutinib (ACP-196) is an irreversible second-generation BTK inhibitor.
In vitro activity: In contrast, acalabrutinib did not inhibit phagocytosis significantly at any dose. This study also performed phagocytosis assays in chamber slides, counting phagocytosing macrophages directly under the microscope. As shown in Figure 2B, 10 μM ibrutinib, but not acalabrutinib, significantly inhibited phagocytosis of rituximabopsonized CLL B cells by macrophages. These data confirm previous reports that ibrutinib inhibits antibody-dependent phagocytosis with an IC50 of 1–3 μM. Although monocytes/macrophages express BTK, the lower IC50 for ibrutinib and the fact that acalabrutinib had little effect on phagocytosis indicate that kinases situated downstream of Fcg receptors other than BTK, such as Hck, FgR or Lyn, and reported to be differentially inhibited by acalabrutinib and BTK,1 may be involved in this phenomenon. This hypothesis does, however, remain to be investigated in detail. Reference: Haematologica. 2017 Oct; 102(10): e400–e403. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622871/
In vivo activity: Two doses of 15 mg/kg of acalabrutinib completely inhibited anaphylactic responses during moderate PSA (20 μg NP-BSA challenge) with an average maximum body temperature decline of –0.369°C and 0% mortality compared with treatment with vehicle (average maximum temperature decline of –3.678°C and 11% mortality; P = 0.0015 by 2-way ANOVA; Figure 6A). Mice receiving this dose of acalabrutinib also showed no increase in clinical score during PSA; consequently, based on scoring and core temperature, their PSA response was not significantly different from that of mice sham-sensitized with PBS instead of IgE. Two lower doses of 1.5 mg/kg of acalabrutinib provided partial protection compared with vehicle (average maximum temperature drop of –2.577°C). Reference: J Clin Invest. 2020 Sep 1; 130(9): 4759–4770. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456252/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 81.0 174.0
DMSO:PBS (pH 7.2) (1:1) 0.5 1.07
DMF 25.0 53.07
Ethanol 37.5 80.56

Preparing Stock Solutions

The following data is based on the product molecular weight 465.52 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Series J, Garcia C, Levade M, Viaud J, Sié P, Ysebaert L, Payrastre B. Differences and similarities in the effects of ibrutinib and acalabrutinib on platelet functions. Haematologica. 2019 Nov;104(11):2292-2299. doi: 10.3324/haematol.2018.207183. Epub 2019 Feb 28. PMID: 30819914; PMCID: PMC6821604. 2. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica. 2017 Oct;102(10):e400-e403. doi: 10.3324/haematol.2017.169334. Epub 2017 Jun 22. PMID: 28642301; PMCID: PMC5622871. 3. Dispenza MC, Krier-Burris RA, Chhiba KD, Undem BJ, Robida PA, Bochner BS. Bruton's tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis. J Clin Invest. 2020 Sep 1;130(9):4759-4770. doi: 10.1172/JCI138448. PMID: 32484802; PMCID: PMC7456252. 4. Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, Mantel R, Smith LL, McClanahan F, Harrington BK, Colomer D, Covey T, Byrd JC, Izumi R, Kaptein A, Ulrich R, Johnson AJ, Lannutti BJ, Wiestner A, Woyach JA. The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Clin Cancer Res. 2017 Jun 1;23(11):2831-2841. doi: 10.1158/1078-0432.CCR-16-0463. Epub 2016 Nov 30. PMID: 27903679; PMCID: PMC5548968.
In vitro protocol: 1. Series J, Garcia C, Levade M, Viaud J, Sié P, Ysebaert L, Payrastre B. Differences and similarities in the effects of ibrutinib and acalabrutinib on platelet functions. Haematologica. 2019 Nov;104(11):2292-2299. doi: 10.3324/haematol.2018.207183. Epub 2019 Feb 28. PMID: 30819914; PMCID: PMC6821604. 2. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica. 2017 Oct;102(10):e400-e403. doi: 10.3324/haematol.2017.169334. Epub 2017 Jun 22. PMID: 28642301; PMCID: PMC5622871.
In vivo protocol: 1. Dispenza MC, Krier-Burris RA, Chhiba KD, Undem BJ, Robida PA, Bochner BS. Bruton's tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis. J Clin Invest. 2020 Sep 1;130(9):4759-4770. doi: 10.1172/JCI138448. PMID: 32484802; PMCID: PMC7456252. 2. Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, Mantel R, Smith LL, McClanahan F, Harrington BK, Colomer D, Covey T, Byrd JC, Izumi R, Kaptein A, Ulrich R, Johnson AJ, Lannutti BJ, Wiestner A, Woyach JA. The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Clin Cancer Res. 2017 Jun 1;23(11):2831-2841. doi: 10.1158/1078-0432.CCR-16-0463. Epub 2016 Nov 30. PMID: 27903679; PMCID: PMC5548968.

Molarity Calculator

Calculate the mass, volume, or concentration required for a solution.
=
x
x
g/mol

*When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and SDS / CoA (available online).

Reconstitution Calculator

The reconstitution calculator allows you to quickly calculate the volume of a reagent to reconstitute your vial. Simply enter the mass of reagent and the target concentration and the calculator will determine the rest.

=
÷

Dilution Calculator

Calculate the dilution required to prepare a stock solution.
x
=
x

1: Maly J, Blachly JS. Chronic Lymphocytic Leukemia: Exploiting Vulnerabilities with Targeted Agents. Curr Hematol Malig Rep. 2016 Feb 11. [Epub ahead of print] PubMed PMID: 26893063.

2: Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7. PubMed PMID: 26641137.



Additional Information

Acalabrutinib is a potent and selective BTK (Bruton's tyrosine kinase) inhibitor. BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. BTK inhibitors targeting B cell receptor signaling and other survival mechanism showed great promise for the treatment of chronic lymphocytic leukemia (CLL)s holds great promise.

As of 2015 it is in late stage clinical trials for relapsed chronic lymphocytic leukemia. Interim results are encouraging : 95% overall response rate. It is also in another 20 clinical trials (alone and in combination) for various cancers.